tbuckley/cabot-search huggingface dataset:
N6‐methyladenosine‐modified <i>DBT</i> alleviates lipid accumulation and inhibits tumor progression in clear cell renal cell carcinoma through the ANXA2/YAP axis‐regulated Hippo pathway
Authors: Daojia Miao, Qi Wang, Jian Shi, Qingyang Lv, Diaoyi Tan, Chuanyi Zhao, Zhiyong Xiong, Xiaoping Zhang
Journal: Cancer Communications (2023)

The mechanism of metabolism reprogramming is an unsolved problem in clear cell renal cell carcinoma (ccRCC). Recently, it was discovered that the Hippo pathway altered tumor metabolism and promoted tumor progression. Thus, this study aimed at identifying key regulators of metabolism reprogramming and the Hippo pathway in ccRCC and pinpointing potential therapeutic targets for ccRCC patients.Hippo-related gene sets and metabolic gene sets were used to screen potential regulators of the Hippo pathway in ccRCC. Public databases and samples from patients were applied to investigate the association of dihydrolipoamide branched chain transacylase E2 (DBT) with ccRCC and Hippo signaling. The role of DBT was confirmed by gain or loss of function assays in vitro and in vivo. Mechanistic results were yielded by luciferase reporter assay, immunoprecipitation, mass spectroscopy, and mutational studies.DBT was confirmed as a Hippo-related marker with significant prognostic predictive value, and its downregulation was caused by methyltransferase-like-3 (METTL3)-mediated N6-methyladenosine (m6 A) modification in ccRCC. Functional studies specified DBT as a tumor suppressor for inhibiting tumor progression and correcting the lipid metabolism disorder in ccRCC. Mechanistic findings revealed that annexin A2 (ANXA2) interacted with the lipoyl-binding domain of DBT to activate Hippo signaling which led to decreased nuclear localization of yes1-associated transcriptional regulator (YAP) and transcriptional repression of lipogenic genes.This study demonstrated a tumor-suppressive role for the DBT/ANXA2/YAP axis-regulated Hippo signaling and suggested DBT as a potential target for pharmaceutical intervention in ccRCC.
Firearm Storage Practices—What Constitutes Safe?
Authors: Ali Rowhani-Rahbar
Journal: JAMA Network Open (2023)

Michael D. Anestis, PhD; Jayna Moceri-Brooks, PhD; Rachel L. Johnson, MS; Craig J. Bryan, PsyD, ABPP; Ian H. Stanley, PhD; Jessica T. Buck-Atkinson, MPH; Justin C. Baker, PhD, ABPP; Marian E. Betz, MD, MPH
2022 EULAR points to consider for the measurement, reporting and application of IFN-I pathway activation assays in clinical research and practice
Authors: Javier Rodríguez-Carrio, Agata Burska, Philip G Conaghan, Willem A Dik, Robert Biesen, Maija-Leena Eloranta, Giulio Cavalli, Marianne Visser, Dimitrios T Boumpas, George Bertsias, Marie Wahren-Herlenius, Jan Rehwinkel, Marie-Louise Frémond, Mary K Crow, Lars Rönnblom, Marjan A Versnel, Edward M Vital
Journal: Annals of the Rheumatic Diseases (2023)

Type I interferons (IFN-Is) play a role in a broad range of rheumatic and musculoskeletal diseases (RMDs), and compelling evidence suggests that their measurement could have clinical value, although testing has not progressed into clinical settings. To develop evidence-based points to consider (PtC) for the measurement and reporting of IFN-I assays in clinical research and to determine their potential clinical utility. EULAR standardised operating procedures were followed. A task force including rheumatologists, immunologists, translational scientists and a patient partner was formed. Two systematic reviews were conducted to address methodological and clinical questions. PtC were formulated based on the retrieved evidence and expert opinion. Level of evidence and agreement was determined. Two overarching principles and 11 PtC were defined. The first set (PtC 1-4) concerned terminology, assay characteristics and reporting practices to enable more consistent reporting and facilitate translation and collaborations. The second set (PtC 5-11) addressed clinical applications for diagnosis and outcome assessments, including disease activity, prognosis and prediction of treatment response. The mean level of agreement was generally high, mainly in the first PtC set and for clinical applications in systemic lupus erythematosus. Harmonisation of assay methodology and clinical validation were key points for the research agenda. IFN-I assays have a high potential for implementation in the clinical management of RMDs. Uptake of these PtC will facilitate the progress of IFN-I assays into clinical practice and may be also of interest beyond rheumatology.
The effect of supervision on community health workers’ effectiveness with households in rural South Africa: A cluster randomized controlled trial
Authors: Mary Jane Rotheram-Borus, Karl W. le Roux, Peter Norwood, Linnea Stansert Katzen, Andre Snyman, Ingrid le Roux, Elaine Dippenaar, Mark Tomlinson
Journal: PLoS Medicine (2023)

Community health workers (CHWs) can supplement professional medical providers, especially in rural settings where resources are particularly scarce. Yet, outcomes of studies evaluating CHWs effectiveness have been highly variable and lack impact when scaled nationally. This study examines if child and maternal outcomes are better when existing government CHWs, who are perinatal home visitors, receive ongoing enhanced supervision and monitoring, compared to standard care.A cluster randomized controlled effectiveness trial was conducted comparing outcomes over 2 years when different supervision and support are provided. Primary health clinics were randomized by clinic to receive monitoring and supervision from either (1) existing supervisors (Standard Care (SC); n = 4 clinics, 23 CHWs, 392 mothers); or (2) supervisors from a nongovernmental organization that provided enhanced monitoring and supervision (Accountable Care [AC]; n = 4 clinic areas, 20 CHWs, 423 mothers). Assessments were conducted during pregnancy and at 3, 6, 15, and 24 months post-birth with high retention rates (76% to 86%). The primary outcome was the number of statistically significant intervention effects among 13 outcomes of interest; this approach allowed us to evaluate the intervention holistically while accounting for correlation among the 13 outcomes and considering multiple comparisons. The observed benefits were not statistically significant and did not show the AC's efficacy over the SC. Only the antiretroviral (ARV) adherence effect met the significance threshold established a priori (SC mean 2.3, AC mean 2.9, p < 0.025; 95% CI = [0.157, 1.576]). However, for 11 of the 13 outcomes, we observed an improvement in the AC compared to the SC. While the observed outcomes were not statistically significant, benefits were observed for 4 outcomes: increasing breastfeeding for 6 months, reducing malnutrition, increasing ARV adherence, and improving developmental milestones. The major study limitation was utilizing existing CHWs and being limited to a sample of 8 clinics. There were no major study-related adverse events.Supervision and monitoring were insufficient to improve CHWs' impact on maternal and child outcomes. Alternative strategies for staff recruitment and narrowing the intervention outcomes to the specific local community problems are needed for consistently high impact.Clinicaltrials.gov, NCT02957799.
Implications of the new ERS/ATS standards on the interpretation of lung function tests
Authors: Paul Desbordes, Maarten De Vos, Julie Maes, Frans de Jongh, Karl Sylvester, Claus Franz Vogelmeier, Anh Tuan Dinh-Xuan, Jann Mortensen, Wim Janssens, Marko Topalovic
Journal: European Respiratory Journal (2023)

<b>Introduced granularity results in a more accurate lung function description and may improve clinical practice, but at the price of complexity. This may have a significant impact on how clinicians classify their patients and may affect their interventions.</b>https://bit.ly/3xIf1g3
Site of vulnerability on SARS-CoV-2 spike induces broadly protective antibody against antigenically distinct Omicron subvariants
Authors: Siriruk Changrob, Peter J. Halfmann, Hejun Liu, Jonathan L. Torres, Joshua J.C. McGrath, Gabriel Ozorowski, Lei Li, G. Dewey Wilbanks, Makoto Kuroda, Tadashi Maemura, Min Huang, Nai-Ying Zheng, Hannah L. Turner, Steven A. Erickson, Yanbin Fu, Atsuhiro Yasuhara, Gagandeep Singh, Brian Monahan, Jacob Mauldin, Komal Srivastava, Viviana Simon, Florian Krammer, D. Noah Sather, Andrew B. Ward, Ian A. Wilson, Yoshihiro Kawaoka, Patrick C. Wilson
Journal: Journal of Clinical Investigation (2023)

The rapid evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants has emphasized the need to identify antibodies with broad neutralizing capabilities to inform future monoclonal therapies and vaccination strategies. Herein, we identified S728-1157, a broadly neutralizing antibody (bnAb) targeting the receptor-binding site (RBS) that was derived from an individual previously infected with WT SARS-CoV-2 prior to the spread of variants of concern (VOCs). S728-1157 demonstrated broad cross-neutralization of all dominant variants, including D614G, Beta, Delta, Kappa, Mu, and Omicron (BA.1/BA.2/BA.2.75/BA.4/BA.5/BL.1/XBB). Furthermore, S728-1157 protected hamsters against in vivo challenges with WT, Delta, and BA.1 viruses. Structural analysis showed that this antibody targets a class 1/RBS-A epitope in the receptor binding domain via multiple hydrophobic and polar interactions with its heavy chain complementarity determining region 3 (CDR-H3), in addition to common motifs in CDR-H1/CDR-H2 of class 1/RBS-A antibodies. Importantly, this epitope was more readily accessible in the open and prefusion state, or in the hexaproline (6P)-stabilized spike constructs, as compared with diproline (2P) constructs. Overall, S728-1157 demonstrates broad therapeutic potential and may inform target-driven vaccine designs against future SARS-CoV-2 variants.
Time Trends and Variation in the Use of Active Surveillance for Management of Low-risk Prostate Cancer in the US
Authors: Matthew R. Cooperberg, William Meeks, Raymond Fang, Franklin D. Gaylis, William J. Catalona, Danil V. Makarov
Journal: JAMA Network Open (2023)

Importance Active surveillance (AS) is endorsed by clinical guidelines as the preferred management strategy for low-risk prostate cancer, but its use in contemporary clinical practice remains incompletely defined. Objective To characterize trends over time and practice- and practitioner-level variation in the use of AS in a large, national disease registry. Design, Setting, and Participants This retrospective analysis of a prospective cohort study included men with low-risk prostate cancer, defined as prostate-specific antigen (PSA) less than 10 ng/mL, Gleason grade group 1, and clinical stage T1c or T2a, newly diagnosed between January 1, 2014, and June 1, 2021. Patients were identified in the American Urological Association (AUA) Quality (AQUA) Registry, a large quality reporting registry including data from 1945 urology practitioners at 349 practices across 48 US states and territories, comprising more than 8.5 million unique patients. Data are collected automatically from electronic health record systems at participating practices. Exposures Exposures of interest included patient age, race, and PSA level, as well as urology practice and individual urology practitioners. Main Outcomes and Measures The outcome of interest was the use of AS as primary treatment. Treatment was determined through analysis of electronic health record structured and unstructured clinical data and determination of surveillance based on follow-up testing with at least 1 PSA level remaining greater than 1.0 ng/mL. Results A total of 20 809 patients in AQUA were diagnosed with low-risk prostate cancer and had known primary treatment. The median age was 65 (IQR, 59-70) years; 31 (0.1%) were American Indian or Alaska Native; 148 (0.7%) were Asian or Pacific Islander; 1855 (8.9%) were Black; 8351 (40.1%) were White; 169 (0.8%) were of other race or ethnicity; and 10 255 (49.3%) were missing information on race or ethnicity. Rates of AS increased sharply and consistently from 26.5% in 2014 to 59.6% in 2021. However, use of AS varied from 4.0% to 78.0% at the urology practice level and from 0% to 100% at the practitioner level. On multivariable analysis, year of diagnosis was the variable most strongly associated with AS; age, race, and PSA value at diagnosis were all also associated with odds of surveillance. Conclusions and Relevance This cohort study of AS rates in the AQUA Registry found that national, community-based rates of AS have increased but remain suboptimal, and wide variation persists across practices and practitioners. Continued progress on this critical quality indicator is essential to minimize overtreatment of low-risk prostate cancer and by extension to improve the benefit-to-harm ratio of national prostate cancer early detection efforts.
Emerging and Legacy Perfluoroalkyl Substances in Breastfed Chinese Infants: Renal Clearance, Body Burden, and Implications
Authors: Jingzhi Yao, Zhaomin Dong, Lulin Jiang, Yitao Pan, Meirong Zhao, Xiaoxia Bai, Jiayin Dai
Journal: Environmental Health Perspectives (2023)

Background: Human breast milk is a primary route of exposure to perfluoroalkyl substances (PFAS) in infants. To understand the associated risks, the occurrence of PFAS in human milk and the toxicokinetics of PFAS in infants need to be addressed. Objectives: We determined levels of emerging and legacy PFAS in human milk and urine samples from Chinese breastfed infants, estimated renal clearance, and predicted infant serum PFAS levels. Methods: In total, human milk samples were collected from 1,151 lactating mothers in 21 cities in China. In addition, 80 paired infant cord blood and urine samples were obtained from two cities. Nine emerging PFAS and 13 legacy PFAS were analyzed in the samples using ultra high-performance liquid chromatography tandem mass spectrometry. Renal clearance rates (CLrenals) of PFAS were estimated in the paired samples. PFAS serum concentrations in infants (&lt;1 year of age) were predicted using a first-order pharmacokinetic model. Results: All nine emerging PFAS were detected in human milk, with the detection rates of 6:2 Cl-PFESA, PFMOAA, and PFO5DoDA all exceeding 70%. The level of 6:2 Cl-PFESA in human milk (median concentration=13.6 ng/L) ranked third after PFOA (336 ng/L) and PFOS (49.7 ng/L). The estimated daily intake (EDI) values of PFOA and PFOS exceeded the reference dose (RfD) of 20 ng/kg BW per day recommended by the U.S. Environmental Protection Agency in 78% and 17% of breastfed infant samples, respectively. 6:2 Cl-PFESA had the lowest infant CLrenal (0.009mL/kg BW per day), corresponding to the longest estimated half-life of 49 y. The average half-lives of PFMOAA, PFO2HxA, and PFO3OA were 0.221, 0.075, and 0.304 y, respectively. The CLrenals of PFOA, PFNA, and PFDA were slower in infants than in adults. Conclusions: Our results demonstrate the widespread occurrence of emerging PFAS in human milk in China. The relatively high EDIs and half-lives of emerging PFAS suggest potential health risks of postnatal exposure in newborns. https://doi.org/10.1289/EHP11403
Secreted <i>Aeromonas</i> GlcNAc binding protein GbpA stimulates epithelial cell proliferation in the zebrafish intestine
Authors: Allison V. Banse, Stephanie VanBeuge, T. Jarrod Smith, Savannah L. Logan, Karen Guillemin
Journal: Gut Microbes (2023)

In response to microbiota colonization, the intestinal epithelia of many animals exhibit increased rates of cell proliferation. We used gnotobiotic larval zebrafish to identify a secreted factor from the mutualist Aeromonas veronii that is sufficient to promote intestinal epithelial cell proliferation. This secreted A. veronii protein is a homologue of the Vibrio cholerae GlcNAc binding protein GbpA, which was identified as a chitin-binding colonization factor in mice. GbpA was subsequently shown to be a lytic polysaccharide monooxygenase (LPMO) that can degrade recalcitrant chitin. Our phenotypic characterization of gbpA deficient A. veronii found no alterations in these cells' biogeography in the zebrafish intestine and only a modest competitive disadvantage in chitin-binding and colonization fitness when competed against the wild-type strain. These results argue against the model of GbpA being a secreted adhesin that binds simultaneously to bacterial cells and GlcNAc, and instead suggests that GbpA is part of a bacterial GlcNAc utilization program. We show that the host proliferative response to GbpA occurs in the absence of bacteria upon exposure of germ-free zebrafish to preparations of native GbpA secreted from either A. veronii or V. cholerae or recombinant A. veronii GbpA. Furthermore, domain 1 of A. veronii GbpA, containing the predicted LPMO activity, is sufficient to stimulate intestinal epithelial proliferation. We propose that intestinal epithelial tissues upregulate their rates of renewal in response to secreted bacterial GbpA proteins as an adaptive strategy for coexisting with bacteria that can degrade glycan constituents of the protective intestinal lining.
Triplet Therapy in Metastatic Hormone-Sensitive Prostate Cancer—Calling Out the “Double Standard”
Authors: Deaglan J. McHugh, Howard I. Scher
Journal: JAMA Oncology (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Interim Clinical Treatment Considerations for Severe Manifestations of Mpox — United States, February 2023
Authors: Agam K. Rao, Caroline A. Schrodt, Faisal S. Minhaj, Michelle A. Waltenburg, Shama Cash-Goldwasser, Yon Yu, Brett W. Petersen, Christina Hutson, Inger K. Damon
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

https://www.cdc.gov/poxvirus/monkeypox/clinicians/pediatric.html;https://www.cdc.gov/poxvirus/monkeypox/clinicians/pregnancy.htmlAbbreviations: CNS = central nervous system; CSF = cerebrospinal fluid; MCM = medical countermeasure; MRI = magnetic resonance imaging; OPXV = orthopoxvirus; PCR = polymerase chain reaction; VIGIV = vaccinia immune globulin intravenous.* This report is a comprehensive synthesis of the heterogeneous evidence and is intended to foster strategic decision-making rather than serve as a prescriptive treatment guideline.† Urgent ophthalmology consultation and management is particularly important for patients with eye pain, vision loss, or worsening ocular symptoms.
Assessment of Firearm Storage Practices in the US, 2022
Authors: Michael D. Anestis, Jayna Moceri-Brooks, Rachel L. Johnson, Craig J. Bryan, Ian H. Stanley, Jessica T. Buck-Atkinson, Justin C. Baker, Marian E. Betz
Journal: JAMA Network Open (2023)

Secure firearm storage may help reduce firearm injury and death. Broad implementation requires more granular assessments of firearm storage practices and greater clarity on circumstances that may prevent or promote the use of locking devices.To develop a more thorough understanding of firearm storage practices, obstacles to using locking devices, and circumstances in which firearm owners would consider locking unsecured firearms.A cross-sectional, nationally representative survey of adults residing in 5 US states who owned firearms was administered online between July 28 and August 8, 2022. Participants were recruited via probability-based sampling.Firearm storage practices were assessed via a matrix provided to participants in which firearm-locking devices were described both via text and images. Locking mechanisms (key/personal identification number [PIN]/dial vs biometric) were specified for each type of device. Obstacles to the use of locking devices and circumstances in which firearm owners would consider locking unsecured firearms were assessed via self-report items developed by the study team.The final weighted sample included 2152 adult (aged ≥18 years), English-speaking firearm owners residing in the US; the sample was predominantly male (66.7%). Among the 2152 firearm owners, 58.3% (95% CI, 55.9%-60.6%) reported storing at least 1 firearm unlocked and hidden, with 17.9% (95% CI, 16.2%-19.8%) reporting storing at least 1 firearm unlocked and unhidden. Gun safes were the most frequently used device both among participants who use keyed/PIN/dial locking mechanisms (32.4%; 95% CI, 30.2%-34.7%) and those who use biometric locking mechanisms (15.6%; 95% CI, 13.9%-17.5%). Those who do not store firearms locked most frequently noted a belief that locks are unnecessary (49.3%; 95% CI, 45.5%-53.1%) and a fear that locks would prevent quick access in an emergency (44.8%; 95% CI, 41.1%-48.7%) as obstacles to lock usage. Preventing access by children was the most often reported circumstance in which firearm owners would consider locking unsecured firearms (48.5%; 95% CI, 45.6%-51.4%).In this survey study of 2152 firearm owners, consistent with prior research, unsecure firearm storage was common. Firearm owners appeared to prefer gun safes relative to cable locks and trigger locks, indicating that locking device distribution programs may not match firearm owners' preferences. Broad implementation of secure firearm storage may require addressing disproportionate fears of home intruders and increasing awareness of the risks associated with household firearm access. Furthermore, implementation efforts may hinge on broader awareness of the risks of ready firearm access beyond unauthorized access by children.
State Variation in Racial and Ethnic Disparities in Incidence of Triple-Negative Breast Cancer Among US Women
Authors: Hyuna Sung, Daniel Wiese, Ismail Jatoi, Ahmedin Jemal
Journal: JAMA Oncology (2023)

There are few data on state variation in racial and ethnic disparities in incidence of triple-negative breast cancer (TNBC) in the US, limiting the ability to inform state-level health policy developments toward breast cancer equity.
Estimated Incidence and Mortality of Stroke in China
Authors: Mingxue Jing, Lena X. Y. Bao, Raymond C. S. Seet
Journal: JAMA Network Open (2023)

Wen-Jun Tu, MD; Zhenping Zhao, PhD; Peng Yin, PhD; Lei Cao, MM; Jingsheng Zeng, MD; Huisheng Chen, MD; Dongsheng Fan, MD; Qi Fang, MD; Pei Gao, PhD; Yuxiang Gu, MD; Guojun Tan, MD; Jianfeng Han, MD; Li He, MD; Bo Hu, MD; Yang Hua, MD; Dezhi Kang, MD; Hongyan Li, MD; Jianmin Liu, MD; Yuanli Liu, MD; Min Lou, MD; Benyan Luo, MD; Suyue Pan, MD; Bin Peng, MD; Lijie Ren, MD; Lihua Wang, MD; Jian Wu, MD; Yuming Xu, MD; Yun Xu, MD; Yi Yang, MD; Meng Zhang, MD; Shu Zhang, MD; Liangfu Zhu, MD; Yicheng Zhu, MD; Zixiao Li, MD; Lan Chu, MD; Xiuli An, MD; Lingxiao Wang, MM; Meng Yin, MM; Mei Li, MM; Li Yin, MM; Wei Yan, MM; Chuan Li, MM; Junli Tang, MD; Maigeng Zhou, PhD; Longde Wang, PhD